Idiopathic pulmonary fibrosis (IPF) is a progressive and ultimately fatal disease. Within IPF, however, there exists marked disease heterogeneity as some patients experience a rapidly progressive course while others experience prolonged periods of stability or stepwise declines triggered by disease exacerbations. Unfortunately, there are no accepted means by which patients can be clinically ?phenotyped? into these different disease courses at the time of diagnosis. The ability to predict an individual patient?s pace of progression would greatly impact patient care by enabling better prognostication, individualization of treatment plans, and early evaluation for lung transplantation for those at highest risk of rapidly progressive disease. Such knowledge could also be utilized as a cohort enrichment strategy allowing new IPF therapies to be evaluated in patients at greatest risk of progression thus improving clinical trial feasibility. We hypothesize that disease activity in IPF is driven by ongoing lung injury and that measurements of ongoing lung injury could be utilized to predict prognosis and treatment response. Vascular leak, a cardinal response to tissue injury, has been implicated in the development of IPF. Alveolar-capillary permeability is increased in the lungs of IPF patients, and the extent of this increase has been shown to correlate with disease progression and mortality. We will use the advanced magnetic resonance imaging (MRI) technique of dynamic contrast-enhanced (DCE) MRI to assess vascular permeability in the lungs of IPF patients and healthy volunteers and prospectively evaluate if these MRI-derived measures of lung vascular permeability predict subsequent IPF disease progression. We will also evaluate whether increased plasma levels of soluble Ephrin-B2 (sEphrin-B2), a novel molecular biomarker of lung injury in fibrosis, can identify IPF patients most likely to experience disease progression. Lastly, we will perform lung DCE-MRI prior to and after initiation of anti-fibrotic therapy with nintedanib, which we hypothesize will decrease lung vascular permeability by inhibiting vascular endothelial growth factor (VEGF), to assess whether our MRI-derived lung vascular permeability measures are decreased with treatment. This research will be performed by Dr. Sydney Montesi, a pulmonary and critical care physician at Massachusetts General Hospital, an Instructor of Medicine at Harvard Medical School, and a specialist in the care of patients with pulmonary fibrosis. She will receive first-rate training in advanced lung imaging and biomarker development. She will be exceptionally mentored by Dr. Peter Caravan, a pioneer in molecular imaging of fibrosis, and co-mentored by Dr. David Christiani, an expert in biomarker development for lung injury. She will perform her research in a world-renowned academic center with all required resources available to her. Dr. Montesi?s goal is to become a physician-scientist in patient-oriented research of pulmonary fibrosis. This K23 award will provide her with the training and mentorship to achieve independence and apply for her first R01.